This grant proposal, "IRON fMRI in animal models: improving sensitivity and spatial localization", is an R01 application in response to RFA EB-03-002, "Systems & Methods for Small Animal Imaging". While functional brain mapping by BOLD fMRI is a common neuroscience technique in humans, animal models enable more effective techniques that are not yet available in humans. In particular, iron oxide contrast agents (IRON fMRI) offer remarkable improvements in fMRI sensitivity, appear to provide better spatial localization than the BOLD method, but suffer a somewhat slower temporal resolution than the BOLD method. The goal of the proposed project is to resolve the principal remaining issues concerning the application of IRON fMRI in animal models. Namely, 1) what are the relative merits and IRON and BOLD fMRI at very high magnetic fields, 2) what implications does the IRON temporal response have for rapidly modulated brain activity, and 3) does blood volume produce significantly better spatial localization than BOLD signal? Our hypotheses are 1) the IRON method will fill a critical role in high field fMRI by improving image quality without a loss of sensitivity, 2) intelligent stimulation strategies will mitigate disadvantages of the slow IRON temporal response even for rapidly stimulus modulations, and 3) the IRON method will improve spatial fMRI localization. Detection sensitivity and spatial resolution are among the most critical experimental factors for effective fMRI in small animal models. The proposed experiments address the most important remaining issues concerning IRON fMRI in animal models, and these studies are a logical step in the eventual progression of this powerful technique from pre-clinical studies to clinical utility.